by C.H. Weaver M.D. updated 7/2019
The investigational agent (Upadacitinib) ABT-494, a JAK-1 inhibitor has been reported to be effective for the management of newly diagnosed and refractory moderate-to-severe rheumatoid arthritis (RA) in clinical studies.
Janus-associated kinase 1 (JAK1) inhibitors mediate the signaling of cytokines and growth factors important for blood cell production and immune function. Jakafi® (ruxolitinib) a JAK 1 inhibitor is currently approved for the treatment of some Myleoproliferative Neoplasms.
In rheumatism, however, they are responsible for inflammatory responses. These are curbed by JAK inhibitors. There are two other JAK inhibitors (tofacitinib and baricitinib), which are also used for treating rheumatoid arthritis – but mostly as combination therapy with the standard therapy methotrexate.
Upadacitinib in Refractory RA
Blocking the JAK pathway also appears important for treating the immune response in RA and investigators have begun to report results. AbbVie is developing ABT 494 in RA and has released some early results from their Balance I and II clinical studies.
In the BALANCE-I study, 276 RA patients who had previously had an inadequate response to one or more tumor necrosis factor (TNF) inhibitors received one of four doses of ABT-494 or placebo for 12 weeks. A 20% or greater improvement was seen in a significant proportion of patients in all dosage groups compared to those treated with placebo.
In the BALANCE-II study, 300 RA patients who had experienced an inadequate response to methotrexate were given one of five doses of ABT-494 for 12 weeks, and a significant improvement was reported in all but the lowest dose group.
ABT-494 has the potential to become a useful treatment option for some of the most challenging RA patients, those that have an inadequate response to TNF drugs.
Overall ABT-494 was generally well tolerated and he most common reported side effect was headache, which was reported by fewer than 5% of patients.
In another study 600 RA patients were treated with different doses of upadacitinib and compared. At the daily dose of 15 mg, more than one third of RA patients achieved low disease activity, and, at 30 mg, the proportion was nearly 50%. Overall 12.5% treated at the low dose and around 20% on the higher dose achieved a sustained remission - defined as the complete disappearance of disease activity.
Question should doctors rethink treatment sequence?
This treatment option is so important because RA patients are initially treated with the standard antirheumatic agent methotrexate for six months, and indeed many of them respond very well to this. However, if they do not respond and no remission or at least reduction in disease activity can be achieved, they are given a combined treatment of methotrexate and a biologic agent – frequently anti-TNF, such as e.g. adalimumab, administered by injection, which involves risk factors.
- Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study.” Josef Smolen, Aileen Pangan, Paul Emery, William Rigby, Yoshiya Tanaka, Juan Ignacio Vargas, Ying Zhang, Nemanja Damjanov, Alan Friedman, Ahmed Othman, Heidi Camp, Stanley Cohen. Published Online May 23, 2019. http://dx.doi.org/10.1016/S0140-6736(19)30419-2.